New Therapies for Treating Advanced Melanoma

Research presented at the American Academy of Dermatology’s 70th Annual Meeting

While melanoma, the most serious form of skin can­cer, is highly curable when detected and treated early, the same is not true for more advanced cases of melanoma – particularly when the dis­ease has spread to lymph nodes or other areas of the body.

Recently, two new drugs approved by the U.S. Food and Drug Adminis­tration (vemurafenib and ipilimumab) that target the genetic makeup of mela­noma are showing promise in slowing the progression of this disease and, in some cases, extending survival in peo­ple with advanced melanoma.

Research shows that certain melano­mas have specific genetic abnormalities within the melanoma cells. With targeted therapy, the abnormal gene responsible for these melanomas is targeted in an attempt to undo the damage it is caus­ing the cells. Darrell S. Rigel, MD, FAAD, clinical professor in the department of Dermatology at NYU Langone Medi­cal Center in New York, NY, notes that while a number of targets have been identified, a gene known as BRAF is mutated in 40 to 80 percent of mela­noma cells. This mutation causes the cells to grow uncontrollably and cancer to form.

Vemurafenib
When a BRAF muta­tion is present, a pathway known as the MAP Kinase Pathway essentially gets “stuck” in the “on” position, and the cells start growing very rapidly. The drug vemurafenib attacks the switch of this pathway (or blocks the “on” switch) so that the cells don’t continue to grow uncontrollably. If effective, the cancer is prevented from getting worse.

With targeted therapy, the abnormal gene
responsible for these melanomas is targeted
in an attempt to undo the damage it is
causing the cells.

While not a cure for melanoma, re­searchers found during clinical trials that on average, participants who re­sponded to vemurafenib lived more than six months without the melanoma getting worse.

In some studies, it was found that within six to ten months on average, the melanoma cells develop resistance to the drug. In this case, melanoma cells either develop other Kinase pro­teins to sidestep the pathway, or they simply use another pathway that is not currently active. Either way, they acti­vate to make cells continue to grow.

Ipilimumab
This new targeted ther­apy blocks a specific molecule, which may allow the body to recognize, target, and attack melanoma cells. Researchers now are looking at using ipilimumab in combination with vemurafenib, as they each block two different pathways, with the theory that there is less chance for resistance to occur.

While not a cure for melanoma, re­searchers found during clinical trials that the participants who received only ipilimumab and responded to it lived about 10 months longer. For a few of those given ipilimumab, the results were dramatic. Some have had no signs of cancer for as long as six years.

Side Effects
Dr. Rigel cautions
that people taking vemurafenib or
ipilimumab may experience trouble­some side effects and should be closely monitored by their dermatologist. Stud­ies show that significant rashes have been reported in approximately 40
percent of people using vemurafenib. One-third of those taking vemurafenib developed multiple, aggressive squa­mous cell carcinomas (another common type of skin cancer).

Advice from the American
Academy of Dermatology
“Before vemurafenib and ipilimumab were in­troduced, beating advanced melanoma used to be virtually hopeless, and now there is at least some hope for these patients,” says Dr. Rigel. “Targeted therapy is still in its infancy, but al­ready it has been successful in some cases of advanced melanoma. The tech­nique shows that it will work, and I expect we’ll see even more effective treatments in the future as we fine-
tune our targeting of melanoma.”

The Academy urges everyone to examine their skin regularly. This means looking over your entire body, including your back, scalp, palms, the soles of your feet, and between your toes. If you notice a mole different from others, or which changes, itches, or bleeds, even if it is smaller than six millimeters, you should make an ap­pointment to see a dermatologist.